CN101613392A - A kind of preparation method of hydrocortisone sodium succinate - Google Patents
A kind of preparation method of hydrocortisone sodium succinate Download PDFInfo
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- CN101613392A CN101613392A CN200910065515A CN200910065515A CN101613392A CN 101613392 A CN101613392 A CN 101613392A CN 200910065515 A CN200910065515 A CN 200910065515A CN 200910065515 A CN200910065515 A CN 200910065515A CN 101613392 A CN101613392 A CN 101613392A
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- hydrocortisone
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Abstract
The invention provides a kind of preparation method of hydrocortisone sodium succinate, belong to the medical chemistry field.The preparation method of hydrocortisone sodium succinate provided by the present invention, comprise step: with the hydrocortisone monomester succinate is raw material, add pure water 0-60 ℃ of dissolving, adding soda makes the pH value between 7.5-11.0, continue to drip acetone, after dropwising, at 10-20 ℃ of insulation reaction 1-2 hour, reaction product is added carbon decoloring, filtration, and the concentrating under reduced pressure drying obtains product.This preparation method temperature of reaction is low, speed is fast, be difficult for to produce other impurity in the reaction process, and side reaction is few, and after concentrated the yield height.
Description
One. technical field:
The present invention relates to a kind of preparation method of hydrocortisone sodium succinate, belong to the medical chemistry field.
Two. background technology:
Hydrocortisone sodium succinate is the salt compounds of hydrocortisone, Aeroseb-Dex.Have multiple pharmacological effect such as anti-inflammatory, antianaphylaxis and inhibition immunity.Clinically treatments that are used for acute anaphylactic disease, status asthmaticus, adrenal crisis outbreak, infection toxic shock etc. more.Also be usually used in treating malignant lymphoma.Have following pharmacological action:
(1) anti-inflammatory action: glucocorticosteroid alleviates and prevents to organize reaction to inflammation, thus the performance that reduces inflammation.
(2) immunosuppressive action: prevent or suppress the immune response of cell mesomeric, the anaphylaxis of retardance, and alleviate and formerly send out expansion immunoreactive.
(3) antitoxin, Antishock function: glucocorticosteroid can resist the irritant reaction of bacterial endotoxin to body, alleviates cell injury, the effect of performance protection body.Oral absorption is rapid, and Tmax is 1h, and T1/2 is 1.6h, plasma protein binding ratio 90%.Also can be through skin absorption.Mainly through liver metabolism, minute quantity with original shape through homaluria.
Hydrocortisone sodium succinate, chemical name is: 11 β, 17-dihydroxyl-21-(3-carboxyl-1-propoxyl) pregnant steroid-4-alkene-3,20-diketone ,-sodium salt.Molecular formula is: C
25H
33O
8Na.Molecular weight: 484.52
The salifiable producing and manufacturing technique of traditional hydrocortisone sodium succinate is to be raw material with the hydrocortisone succsinic acid, dissolving back salify in water, and its shortcoming is: industrial scale is little, and yield is low, and the drying cost height is difficult for dry.It is the method for feedstock production hydrocortisone sodium succinate with the hydrocortisone monomester succinate that Chinese patent application numbers 200710057321.5 has been announced a kind of, but this method needs at first and the buffered soln reaction, has increased the complicacy of process.
Three. summary of the invention:
The object of the invention is for providing a kind of preparation method of hydrocortisone sodium succinate cheaply rapidly and efficiently.
The preparation method of a kind of hydrocortisone sodium succinate provided by the present invention, comprise step: with the hydrocortisone monomester succinate is raw material, add pure water 0-60 ℃ of dissolving, adding soda makes pH value between 7.5-11.0, continue to drip acetone, after dropwising, at 10-20 ℃ of insulation reaction 1-2 hour, reaction product is added carbon decoloring, filtration, concentrate drying.Described soda is sodium bicarbonate or sodium hydroxide.The speed that drips acetone is the 1-2.5ml/ branch, and the milliliter number of dropping is 1.8-2.5 times of hydrocortisone monomester succinate gram number.Adopt concentrating under reduced pressure, thickening temperature is lower than 30 ℃, and vacuum is smaller or equal to-0.08MPa.
The preparation method of hydrocortisone sodium succinate provided by the present invention does not use organic solvent, directly reacts in water, has reduced environmental pollution; improved yield, reaction process is stable, and the process time is short, and is simple to operate; constant product quality has reduced production cost, the easily big production of mass-producing.
Four. embodiment:
In order to explain enforcement of the present invention more fully, provide preparation method's embodiment of hydrocortisone monomester succinate.These embodiments only are the elaborations to technology, do not limit the scope of the invention.Selecting for use of soda, preferentially select sodium bicarbonate for use, the vacuum that this patent is explained≤-the 0.08MPa finger pressure is not more than 0.08MPa by force.
Embodiment 1,
The preparation of hydrocortisone monomester succinate: 1Kg hydrocortisone, 1.9kg dimethyl formamide are put in the exsiccant retort, under the 20-25 ℃ of stirring, stirred molten clear.Open interlayer salt solution and be cooled to 10 ± 1 ℃, drop into the 0.22Kg triethylamine, slowly add the 0.8Kg Succinic anhydried again, 15 ± 1 ℃ of reactions of controlled temperature 3.5 hours.Be diluted under whipped state in the 15Kg purified water that is cooled to 2 ℃, 5-8 ℃ left standstill 3 hours, filtered discharging, and highly finished product are white powder, yield 95.2%.
Embodiment 2,
Synthesizing of hydrocortisone sodium succinate: the method with embodiment 1 obtains hydrocortisone monomester succinate 50g, adds in the proportional quantity 200ml purified water, and solvent temperature is 0-10 ℃, and stir about 50min dissolves fully.Add sodium bicarbonate 9g, slowly add proportional quantity acetone 100ml, about 2ml/ component velocity drips, after dropwising, temperature is controlled at 0-10 ℃, insulation reaction 2h, molten gradually clear, add charcoal 2.5g, decolouring 30min, pan filters, concentrating under reduced pressure, T≤30 ℃, vacuum should≤-0.08MPa, be concentrated to hydrocortisone sodium succinate 46.32g, color is white or off-white powder. yield is 92.64%, 170 ℃ of fusing points.
Embodiment 3,
Synthesizing of hydrocortisone sodium succinate: the method with embodiment 1 obtains hydrocortisone monomester succinate 50g, adds in the proportional quantity 165ml purified water, and solvent temperature is 10-20 ℃, and stir about 40min dissolves fully.Hydro-oxidation sodium 4.3g slowly adds proportional quantity acetone 100ml, and about 2ml/ component velocity drips, after dropwising, temperature is controlled at 10-20 ℃, insulation reaction 1.5h, molten gradually clear, add charcoal 2.5g, decolouring 30min, pan filters, concentrating under reduced pressure, T≤30 ℃, vacuum should≤-0.08MPa, be concentrated to hydrocortisone sodium succinate 45.86g, color is white or off-white powder. yield is 91.72%, 170 ℃ of fusing points.
Embodiment 4,
Synthesizing of hydrocortisone sodium succinate: the method with embodiment 1 obtains hydrocortisone monomester succinate 50g, adds in the proportional quantity 165ml purified water, and temperature of reaction is 10-20 ℃, and stir about 40min dissolves fully.Add sodium bicarbonate 9g, slowly add acetone 100ml, about 2ml/ divides dropping, after dropwising, temperature is controlled at 10-20 ℃, insulation reaction 1.5h, molten gradually clear, add charcoal 2.5g, decolouring 30min, pan filters, concentrating under reduced pressure, T≤30 ℃, vacuum should≤-0.08MPa, be concentrated to hydrocortisone sodium succinate 47.25g, color is white or off-white powder. yield is 94.5%, 170.5 ℃ of fusing points.
Embodiment 5,
Synthesizing of hydrocortisone sodium succinate: the method with embodiment 1 obtains hydrocortisone monomester succinate 50g, adds in the proportional quantity 165ml purified water, and temperature of reaction is 20-30 ℃, and stir about 30min dissolves fully.Add sodium bicarbonate 9g, slowly add proportional quantity acetone 100ml, about 2ml/ component velocity drips, after dropwising, temperature is controlled at 10-15 ℃, insulation reaction 1h, molten gradually clear, add charcoal 2.5g, decolouring 30min, pan filters, concentrating under reduced pressure, T≤30 ℃, vacuum should≤-0.08MPa, be concentrated to hydrocortisone sodium succinate 47.4g, color is white or off-white powder. yield is 94.8%, 171 ℃ of fusing points.
Embodiment 6,
Synthesizing of hydrocortisone sodium succinate: the method with embodiment 1 obtains hydrocortisone monomester succinate 50g, adds in the 165ml purified water, and temperature of reaction is 30-40 ℃, and stir about 20min dissolves fully.Add sodium bicarbonate 9g, slowly add proportional quantity acetone 100ml, about 2ml/ component velocity drips, after dropwising, temperature is controlled at 10-15 ℃, insulation reaction 1h, molten gradually clear, add charcoal 2.5g, decolouring 30min, pan filters, concentrating under reduced pressure, T≤30 ℃, vacuum should≤-0.08MPa, be concentrated to hydrocortisone sodium succinate 44.71g, color is white or off-white powder. yield is 89.42%, 170 ℃ of fusing points.
Embodiment 7,
Synthesizing of hydrocortisone sodium succinate: the method with embodiment 1 obtains hydrocortisone monomester succinate 50g, adds in the 165ml purified water, and temperature of reaction is 40-50 ℃, dissolving 20min.Add sodium bicarbonate 9g, slowly add acetone 100ml, about 2ml/ component velocity drips, after dropwising, temperature is controlled at 10-15 ℃, insulation reaction 1.5h, molten gradually clear, add charcoal 2.5g, decolouring 30min, pan filters, concentrating under reduced pressure, T≤30 ℃, vacuum should≤-0.08MPa, be concentrated to hydrocortisone sodium succinate 46.32g, color is white or off-white powder. yield is 92.64%, 170.5 ℃ of fusing points.Yield 93%, 171 ℃ of fusing points.
Preparation method's temperature of reaction of hydrocortisone sodium succinate provided by the present invention is low, speed is fast, be difficult for producing other impurity in the reaction process, side reaction is few, and yield height after concentrating, moisture content wherein and other solvent content are low, lay the first stone for the later stage drying, the hydrocortisone sodium succinate of present method preparation meets CP2005 and USP28 standard, can be used for clinical.
After the preferred embodiment that describes in detail, being familiar with this technology personage can be well understood to, can carry out various variations and modification not breaking away under above-mentioned claim and the spirit, all foundations technical spirit of the present invention all belongs to the scope of technical solution of the present invention to any simple modification, equivalent variations and modification that above embodiment did.And the embodiment that the present invention also is not subject in the specification sheets to be given an actual example.
Claims (4)
1. the preparation method of a hydrocortisone sodium succinate is characterized in that, may further comprise the steps:
1) is raw material with the hydrocortisone monomester succinate, adds pure water, add soda and make pH value between 7.5-11.0, continue to drip acetone, after dropwising, at 10-20 ℃ of insulation reaction 1-2 hour 0-60 ℃ of dissolving.
2) reaction product is added carbon decoloring, filter concentrate drying.
2. the preparation method of a kind of hydrocortisone sodium succinate according to claim 1, it is characterized in that: the soda described in the step 1 is sodium bicarbonate or sodium hydroxide.
3.. the preparation method of a kind of hydrocortisone sodium succinate according to claim 1 is characterized in that: the speed that drips acetone in the step 1 is the 1-2.5ml/ branch, and the milliliter number of dropping is 1.8-2.5 times of hydrocortisone monomester succinate gram number.
4.. the preparation method of a kind of hydrocortisone sodium succinate according to claim 1 is characterized in that: adopt concentrating under reduced pressure, thickening temperature to be lower than 30 ℃ in the step 2, vacuum is smaller or equal to-0.08MPa.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102718825A (en) * | 2012-06-28 | 2012-10-10 | 天津生物化学制药有限公司 | Preparation method of hydrocortisone hemisuccinat |
| CN103724383A (en) * | 2012-10-10 | 2014-04-16 | 河南利华制药有限公司 | Drying technology of production of hydrocortisone sodium succinate |
| CN109970834A (en) * | 2019-02-27 | 2019-07-05 | 郑州明泽医药科技有限公司 | A kind of preparation method of hydrocortisone sodium succinate |
| CN112220761A (en) * | 2020-10-20 | 2021-01-15 | 安徽海洋药业有限公司 | Preparation method of hydrocortisone sodium succinate for injection |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101050229A (en) * | 2007-05-11 | 2007-10-10 | 天津市生物化学制药厂 | Method for preparing hydrocortisone sodium succinate |
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2009
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102718825A (en) * | 2012-06-28 | 2012-10-10 | 天津生物化学制药有限公司 | Preparation method of hydrocortisone hemisuccinat |
| CN103724383A (en) * | 2012-10-10 | 2014-04-16 | 河南利华制药有限公司 | Drying technology of production of hydrocortisone sodium succinate |
| CN109970834A (en) * | 2019-02-27 | 2019-07-05 | 郑州明泽医药科技有限公司 | A kind of preparation method of hydrocortisone sodium succinate |
| CN112220761A (en) * | 2020-10-20 | 2021-01-15 | 安徽海洋药业有限公司 | Preparation method of hydrocortisone sodium succinate for injection |
| CN112220761B (en) * | 2020-10-20 | 2022-08-05 | 安徽海洋药业有限公司 | Preparation method of hydrocortisone sodium succinate for injection |
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